Different effects of Alzheimer-associated mutations of presenilin 1 on its processing

Murayama, Ohoshi; Honda, Toshiyuki; Mercken, Marc; Murayama, Miyuki; Yasutake, Kaori; Nihonmatsu, Naomi; Nakazato, Yuko; Michel, Gilles; Song, Shaochuen; Sato, Kazuki; Takahashi, Hiroshi; Takashima, Akihiko

doi:10.1016/s0304-3940(97)00417-5

Cited by 30 publications

(19 citation statements)

References 13 publications

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“…It is accepted that the PS1‐ΔE9 mutant contains a deletion in the cleavage domain and therefore resists endoproteolysis; this observation suggests the possibility that a general processing defect may be important in the pathogenesis of FAD. Transient PS1 cDNA transfections in PC12 cells by others (Mercken et al, 1996; Murayama et al, 1997; Takashima, 1997) with the same PS1 mutants used in this study demonstrated a processing defect similar to our findings in PC12 cells and HNs. Aberrant mutant PS2 protein processing has also been reported; Xia et al (1997) demonstrated defective mutant endoproteolytic cleavage in cell lines that stably overexpressed mutant PS2.…”

Section: Discussionsupporting

confidence: 90%

Processing of Wild‐Type and Mutant Familial Alzheimer’s Disease‐Associated Presenilin‐1 in Cultured Neurons

Weihl¹,

Ghadge²,

Miller³

1999

Journal of Neurochemistry

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Mutations of presenilin (PS)-1, an endoplasmic reticulum/Golgi transmembrane protein, have been associated with early-onset familial Alzheimer's disease (FAD). In mammalian brain, PS1 exists primarily as its processed fragments; however, the role of this cleavage event in PS1 function remains unclear. Although some investigators have shown that mutant PS1 processing is unaltered (with the exception of PS1-⌬E9, which lacks the cleavage site) in stably transfected cells and PS1-FAD transgenic mice, other investigators have reported altered FAD mutant PS1 and PS2 protein processing in transiently transfected cells and human FAD patients. The present study uses recombinant replication-defective adenoviral vectors to transiently express wild-type (WT ) or mutant PS1 in various cells, including primary cultured hippocampal neurons. We show that in contrast to PS1-WT, overexpression of mutant PS1 results in an increased ratio of mutant holoprotein to endoproteolytic products that is dependent on cell type and differentiation state. In addition, mutant PS1 overexpression leads to an increase in caspase-type protease derived fragments above that seen with PS1-WT overexpression. Furthermore, overexpression of at least one mutant significantly alters the processing of coexpressed PS1-WT, suggesting that mutant PS1 may affect PS1-WT function. These findings suggest that a defect in PS1 holoprotein stability may be a general defect seen in cells expressing mutant PS1, especially neuronal cells, and may play a critical role in the pathogenesis of FAD. Key Words: Presenilin-Alzheimer's disease -Proteolytic processing-Recombinant adenoviral vector.

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Section: Discussionsupporting

confidence: 90%

Processing of Wild‐Type and Mutant Familial Alzheimer’s Disease‐Associated Presenilin‐1 in Cultured Neurons

Weihl¹,

Ghadge²,

Miller³

1999

Journal of Neurochemistry

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“…1). The levels of PS1 were quantified by using anti-PS1 antibody, MKAD3.4, which was raised against the N-terminal hydrophilic region of PS1 (29)(30)(31). In human brain extracts, this antibody recognizes a faint 48-kDa band, which corre-FIG.…”

Section: Resultsmentioning

confidence: 99%

Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau

Takashima

Murayama

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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388

263

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Families bearing mutations in the presenilin 1 (PS1) gene develop Alzheimer's disease. Previous studies have shown that the Alzheimer-associated mutations in PS1 increase production of amyloid ␤ protein (A␤ 1-42 ). We now show that PS1 also regulates phosphorylation of the microtubule-associated protein tau. PS1 directly binds tau and a tau kinase, glycogen synthase kinase 3␤ (GSK-3␤). Deletion studies show that both tau and GSK-3␤ bind to the same region of PS1, residues 250-298, whereas the binding domain on tau is the microtubule-binding repeat region. The ability of PS1 to bring tau and GSK-3␤ into close proximity suggests that PS1 may regulate the interaction of tau with GSK-3␤. Mutations in PS1 that cause Alzheimer's disease increase the ability of PS1 to bind GSK-3␤ and, correspondingly, increase its tau-directed kinase activity. We propose that the increased association of GSK-3␤ with mutant PS1 leads to increased phosphorylation of tau.The neuropathological diagnosis of Alzheimer's disease (AD) requires the presence of both senile plaques and neurofibrillary tangles (NFT) (1). Senile plaques are largely composed of amyloid ␤ protein (A␤), whereas NFT are composed of hyperphosphorylated tau organized into filamentous structures termed paired helical filaments (2-4). Mutations on the presenilin 1 (PS1) gene cause an early onset form of AD with an autosomal dominant inheritance pattern (5-7). The role of PS1 in AD is particularly interesting because it has a strong causal relationship to the disease; genetic studies show that mutations for PS1 exhibit 100% penetrance in causing AD (8). Although, the mechanism through which PS1 causes AD is unclear. Mutations in presenilins affect A␤ processing. Recent studies indicate that cell lines, transgenic mice, or patients expressing mutant forms of PS1 show a selective increase in production of A␤ 1-42 (9-12). Mutations in the presenilins also activate apoptotic pathways and render neurons more vulnerable to stressors, such as A␤ neurotoxicity (13-16). The ability of PS1 to potentiate A␤ toxicity raises the possibility that PS1 interacts with glycogen synthase kinase 3␤ (GSK-3␤), which we previously have shown to be involved in A␤-mediated cell death (17-20). The enzyme GSK-3␤ also has been implicated in AD because this kinase is one of a group of proline-directed kinases that can phosphorylate the microtubule-associated protein tau, to generate a precursor to NFTs, termed paired helical filaments-tau (21,22). PS1 (23-26) and GSK-3␤ (27, 28) can be found in association with NFTs in the Alzheimer brain, which further suggests that there may be a physiological connection between PS1, GSK-3␤, and tau. To pursue these intriguing connections, we investigated whether PS1 might directly associate with GSK-3␤ and tau. MATERIALS AND METHODSPreparation of Brain Samples. Human brain cortex was obtained at autopsy from patients ranging in age from 44 to 88 years old. Twenty-one samples, from donors age 44-79, showed no evidence of neurological disorders, whereas two sa...

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“…Okochi and colleagues (1997) reported a lack of association between a series of PS1 mutations and their susceptibility to processing, which was in agreement with a recent work indicating that PS1 fragments accumulate in the brain of patients harboring the I143T and G384A mutations to an extent similar to that observed in control or sporadic brains . Conversely, Murayama et al (1997) showed that Cys410 Ͼ Tyr PS1 resisted proteolysis, whereas Gly384 3 Ala or Leu392 3 Val did not. Mutations Met146 3 Val and Ala246 3 Glu also impair PS processing in PC12 cells .…”

Section: B Cell Biology Of Presenilinsmentioning

confidence: 96%

Notice of Concern

Abernethy¹

2006

Pharmacol Rev

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Different effects of Alzheimer-associated mutations of presenilin 1 on its processing

Cited by 30 publications

References 13 publications

Processing of Wild‐Type and Mutant Familial Alzheimer’s Disease‐Associated Presenilin‐1 in Cultured Neurons

Processing of Wild‐Type and Mutant Familial Alzheimer’s Disease‐Associated Presenilin‐1 in Cultured Neurons

Presenilin 1 associates with glycogen synthase kinase-3β and its substrate tau

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